The Japanese archipelago extends from a subtropical zone to a temperate zone and has a warm climate high in humidity, which is liable to facilitate propagation of fungi such as molds. In addition, due to westernization of clothes, people are now accustomed to wearing shoes on feet. Accordingly, a foot serves as a favorable environment for the propagation of the fungi, leading to mycotic skin diseases that are serious social issues nowadays. Of those, onychomycosis has a low complete cure rate and high relapsing and reinfection rates. Therefore, an effective therapy has been demanded.
Conventionally, treatments mainly using tolnaftate formulations have been conducted on such diseases. In recent years, imidazole-based antifungal agents, such as bifonazole and itraconazole, are mainly used.
As the imidazole-based antifungal agents, there are commercially available imidazole-based antifungal agents such as those represented by the general formula (1) described below, specifically, luliconazole represented by the structural formula (1) below and lanoconazole represented by the structural formula (2) below. A commercially available product called “Lulicon” (registered trademark) is also present (e.g., see Patent Document 1 and Patent Document 2).
The luliconazole is an imidazole-based antifungal agent having optical activity with a wide antifungal spectrum, in particular, shows remarkable antifungal activity against dermatophytes. In addition, the luliconazole is also characterized in that its retention in the stratum corneum is extremely high, and thus is a compound expected to be applied to treatment of onychomycosis. Like other imidazole-based antifungal agents, however, luliconazole and lanoconazole are agents having problems in their solubility, so there is a need of using a solvent for their preparation. On the other hand, in some cases, the characteristic features of luliconazole may include a risk of a decrease in its optical purity when it is stored in a dissolved state under severe circumstances due to a type of a solvent used for dissolution, temperature, acid and base, or the like. Besides, such a decrease in optical purity may relate to a solvent. In other words, with regard to a pharmaceutical composition for external use containing luliconazole and/or a salt thereof, it is desirable to provide means for increasing the solubility thereof while suppressing a decrease in optical purity even under severe environment.
A decrease in optical purity is a common phenomenon, which sometimes occurs in an optically active compound according to storage conditions, particularly under severe conditions at high temperature. However, no means for suppressing the phenomenon is known.
Heretofore, in a pharmaceutical technology for antifungal agents, various studies have been conducted for increasing the solubility thereof (see, for example, Patent Documents 3 to 5). However, the antifungal agents to be dissolved show increases different in their solubility. Therefore, the effect of one of them cannot be directly applied to the other compounds. Among the solvents, a solvent that acts to prevent the optically active compound from a decrease in optical purity has not yet been known.
On the other hand, as a pharmaceutical preparation containing luliconazole and/or a salt thereof, a pharmaceutical preparation containing a film-forming agent and a polyoxypropylene/polyoxyethylene copolymer has been known (see, for example, Patent Document 6), but one containing N-methyl-2-pyrrolidone, propylene carbonate, or crotamiton has not been known at all. In addition, a basic process for manufacturing an imidazole-based compound is also already known in the art (see, for example, Patent Document 7):
where X represents a hydrogen atom or a chloride atom.

    Patent Document 1: JP 10-226686 A    Patent Document 2: JP 2-275877 A    Patent Document 3: JP 5-306223 A    Patent Document 4: JP 7-206711 A    Patent Document 5: WO96/11710    Patent Document 6: WO03/105841    Patent Document 7: JP 62-93227 A